Cell death plays an important role in every sort of life phenomenon. In particular, research on cell death in the nervous system is expected as useful to reveal general mechanism of cell death, as well as to develop therapeutic and preventive treatment of diseases relating to the brain and nerve which will presumably be more increasing in the future due to the presently progressing aging society.
The relationship between cell death and information transfer pathway has been being elucidated very recently. Especially as for Fas (CD95), TNF receptors and the like, various molecules have been isolated and identified which participate in information transfer starting from signal receptors of cell death and leading to caspase, a protein that executes cell death.
In nerve cells, information on proliferation and differentiation is transferred through the nerve growth factor (NGF), and it has become apparent recently that NGF induces cell death in some cells. Namely, it has been reported that NGF promotes nerve cell survival through the trkA receptor as a high-affinity receptor, whilst NGF induces cell death in immature nerve cells expressing only p75NTR as a low-affinity NGF receptor and mature neuroglia cells such as oligodendrocyte. p75NTR belongs to the TNF receptor superfamily from a viewpoint of structural feature, and has the death domain in its molecule similarly to TNF receptor. However, as to p75NTR, participation of information transfer protein such as FADD and TRADD has not been reported, and information transfer to apoptosis has not yet been clearly revealed. The nerve growth factor (NGF) acts on cells of the nervous system and induces signals for cell survival, cell death or cell differentiation. Two receptors, i.e., a high-affinity nerve growth factor receptor (trkA) and a low-affinity one (p75NTR), are known as NGF receptors. However, signal transfer mechanism mediated by p75NTR and molecules participating in the signal transfer have not yet been elucidated sufficiently.
With the progress of study on the signal transfer mechanism mediated by p75NTR, a protein referred to as NADE (p75NTR-associated cell death executor, referred to as “NADE”hereinafter in the specification) was first identified by the research group of Columbia University as a protein which binds to the nerve growth factor receptor (p75NTR) and participates in the induction and regulation of apoptosis (Biol. Chem., 275, pp.17566-17670). It is known that NADE has 124 amino acids in the full length sequence and encodes a protein having the molecular weight of approximately 15 kDa (Hum. Mpl. Genet., 8, 611-619, 1999 reported as Bex8), and that NADE is highly expressed in the brain, heart and lung observed from mRNA level.
As described above, NADE has been elucidated to bind to the nerve growth factor receptor (p75NTR) and participate in the induction and regulation of apoptosis. Identification of a protein which binds to NADE and associates with apoptosis mediated by NADE is expected to be useful for developing medicaments for treatment, prevention and/or diagnosis of apoptosis-associated diseases. However, such proteins have not been identified so far.